The prostaglandins (in the following abbreviated as PG:s) are a new group of biologically active substances affecting many important physiological processes largely by influencing intracellular metabolism. See e.g. E.W. Horton in "Prostaglandins" (Monographs, Endocrinology, Vol. 7, 1972; Springer-Verlag).
The basic chemical structure of the PG:s is a C.sub.20 fatty acid, prostanoic acid, containing a five-membered ring. ##STR1##
Depending on the substituents in the five-membered ring four different abbreviations are used in the literature. ##STR2##
All E-types PG:s have 11.alpha.-hydroxy and 9-keto groups in the cyclopentane ring. In the F-types the 9-keto group is reduced to a (.alpha.or .beta.) hydroxyl group. All the "primary" PG:s contain a 13:14 trans double bond. E.sub.1 and F.sub.1 compounds have only this one double bond the E.sub.2 and F.sub.2 molecules have an additional 5:6 cis double bond and the E.sub.3 and F.sub.3 a further cis double bond between 17 and 18. All naturally occurring PG:s found today have a 15(S)-hydroxy group. 9.alpha., 11.alpha., 15(S)-tri hydroxy-5-cis, 13-transprostadienoic acid has for example, been called prostaglandin F.sub.2.alpha. and further abbreviated as PGF.sub.2.alpha..
Details about the chemistry of the PG:s are found, e.g. in a review by P.W. Ramwell et al., in "Progress in the chemistry of fats and other lipids" vol. IX, p. 231.
It is also known that compounds with a structure related to the naturally occurring PG:s can have similar effects. See e.g. P.W. Ramwell et al., Nature 221 (1969) 1251, W. Lippman, J. Pharm. Pharmacol. 22 (1970) 65, J. Fried et al., J. Am. Chem. Soc. 97 (1971) 7319 and N.S. Crossley, Tetrahedron Letters (1971), 3327.
Evidence that PG:s are involved in a large number of physiological and pathological processes is rapidly accumulating. Two major areas, where these compounds play an important physiological role, are the control of fertility and the regulation of blood flow. Further, the PG:s have potent pharmacological actions on smooth muscle in various other organs such as the gastrointestinal and the respiratory tracts. They are also involved in the events following nerve stimulation, both centrally and in the periphery, as well as in the process of lipolysis. There are also indications that PG:s play an important role in different ophthalmologic disorders.
In the area of reproduction PG:s are involved in several ways. It is known, for instance, that sufficient amounts of PG:s to affect the female genital-tract smooth muscles are delivered with the semen and thereby probably promote conception. At full term the levels of PG:s in plasma and amniotic fluid are increased which in turn initiates the onset of labour. This latter effect of PG:s is presently being used therapeutically.
The circulatory effects of PG:s are as a rule vasodepressive, although PGF in some instances may cause a rise of the blood-pressure. The way in which PG:s normally contribute to blood-flow regulation has not yet been elucidated.
In the gastrointestinal tract PG:s generally cause contraction of the smooth muscle. Certain kinds of diarrhoea are believed to be caused by high plasma levels of PG:s. In the lungs PGF causes bronchoconstriction, while PGE has the opposite effect. At nerve stimulation PG:s are released and, at least in peripheral nerves, seem to counteract the result of the stimulation.
The effects of PG:s are generally obtained with very small amounts of the compounds, and this observation, together with the fact that PG:s are widely distributed in the organism point to an important role of those compounds in homeostatic mechanisms. However, although so many important pharmacological effects of PG:s are known, the exact nature of their physiological involvements is poorly understood. This is in part due to the fact that no suitable inhibitory compound has so far been available.
Having very pronounced physiological and pharmacological effects the PG:s could safely be anticipated also to play an important role in pathological conditions. Accordingly, there is now rapidly growing evidence for this, a fact that further emphasizes the need for prostaglandin-inhibitory agents. Thus, PG:s are involved in inflammatory processes of various kinds, such as burns, contact dermatitis and anaphylactic reactions. In these cases PG:s have been suggested to be mediators of the reaction. One important condition, for example, in which PG:s are considered to be of etiological significance, is bronchial asthma. In this connection it is of interest to mention that a substance, chemically and pharmacologically closely related to the prostaglandins, namely Slow Reacting Substance (SRS, Cf. Strandberg, K. and Uvnas, B. in Acta Physiol. Scand. 82 (1971) p. 358), is also produced during anaphylaxis, e.g. in bronchial asthma. A possibility to counteract the effect of this substance is thus also highly desirable.
Against the background of the above information it is evident that major therapeutic advances may result from the use of prostaglandin-inhibitory substances. Inhibition of various inflammatory reactions, improvement of bronchial asthma, regulation of bloodflow, control of gastrointestinal hypermotility are a few examples of expected therapeutic effects of such compounds. With increasing knowledge about the functions of PG:s the usefulness of inhibitors therefore will no doubt become still more apparent. Not only will conditions characterized by an excessive formation of PG:s be improved, but it is also possible to influence certain normal physiological processes when so desired, such as for example the conception.
Therapeutic advances may further result from administering esters of this invention before, at the same time or after the administration of PG:s in order to prevent side-effects caused by the PG:s, e.g. diarrhoea, nausea, vomiting, local tissue reactions and pyrexia.
The expression "prostaglandins" (PG:s) as used in this disclosure is intended to cover prostaglandins and related structures as indicated above of natural as well as synthetic origin.
In addition the esters of this invention exert an inhibitory action on the hormone stimulated formation of adenosine 3', 5'-monophosphate (cyclic AMP). Cyclic AMP is formed from adenosine 5'-triphosphoric acid (ATP) by the action of adenyl cyclase, an enzyme system contained in the plasma membrane. The hormones influence this enzyme complex and thereby the intracellular concentration of cyclic AMP. The cells respond to the changes in cyclic AMP levels with whatever mechanism the different cells have available. It seems likely that compounds which influence the formation of cyclic AMP will be of therapeutic value, when increasing knowledge about the cellular dysfunction at different pathological conditions will be available. See e.g. G.A. Robinson et. al. in "Cyclic AMP", Academic Press, 1971.
Some antagonists of prostaglandins have already been described. J. Fried et. al., nature 223 (1969) 208, found that 7-oxa-prostaglandin-like compounds with 6-membered rings inhibited prostaglandin E.sub.1 (PGE.sub.1).
A derivative of dibenzoxazepine was found to antagonize PGE.sub.2 (J.H. Sanner in Arch. int. Pharmacodyn. 180 (1969) 46.)
A high molecular weight polyester between phloretin and phosphoric acid was also found to have a prostaglandin-blocking activity (K.E. Eakins et al. Brit. J. Pharmac. 39 (1970) 556), and in addition to be an antagonist of Slow Reacting Substance (SRS) (Mathe, A.A., and Strandberg, K. in Acta physiol. scand. 82 (1971) 460).
This polymer, polyphoretin phosphate, was already described by E. Diczfalusy et al. in Acta Chem. Scand. 7 (1953) 913, as a cross-linked high molecular weight enzyme inhibitor. It has an average molecular weight of 15 000, did not dialyze through a cellophane membrane, and was found to be a strong inhibitor of various enzymes e.g. hyaluronidase and alkaline phosphatase.
These materials are complex mixtures of various different polymeric structures in varying proportions (due to the inability to control either the degree of polymerisation or selectively induce such polymerisation at specific reactions sites in view of the availability of numerous possible sites at which polymerisation can occur) and the activity which has been attributed thereto could not be attributed to any specific polymeric structure, much less any specific molecular weight fraction of any certain structures or units thereof, either in theory or in practice, in which latter aspect positive identification of specific active components of the complex polymeric mixture has been impossible.
It has now, surprisingly, been found that certain simple synthetic secondary phosphoric acid esters of the structures shown below are very good selective inhibitors of PG:s and compounds with prostaglandin activities and that they also selectively antagonize the Slow Reacting Substance (SRS). These effects are shown in examples Nos. 22-26.
From the results obtained in these examples it is obvious that the compounds of this invention are useful when it is desired to inhibit the effects caused by various PG:s and also of the effect of SRS.
Example No. 27 shows that the compounds also can prevent or reduce an anaphylactic bronchoconstriction.
The inhibitory effect of esters of this invention on the formation of cyclic AMP is described in example No. 28.
This example shows the usefulness of the compounds to prevent the formation of cyclic AMP and thus improve a condition where an excessive formation of that compound occurs.
In addition the esters of this invention exert a smooth muscle stimulatory activity as demonstrated in examples Nos. 29-31.
Since the compounds of the invention are produced synthetically, they have a definitive structure and are of course substantially free of inactive or lesser active impurities and materials of similar and/or indefinite composition and structure.
In the types of experiments described by Eakins et al. (ibid.) and by Perklev & Ahren (Life Sciences Part I, 10 (1971) 1387) most of the compounds of this invention are much stronger inhibitors against prostaglandins, e.g. E.sub.1 (PGE.sub.1), E.sub.2 (PGE.sub.2), F.sub.1.alpha. (PGF.sub.1.alpha.) and F.sub.2.alpha. (PGF.sub.2.alpha.) than polyphloretin phosphate and they are also superior as antagonists for Slow Reacting Substance (SRS) in the types of experiments described by Mathe and Strandberg (ibid.). In addition the secondary phosphoric acid esters of this invention have no such antienzymatic properties as those described for this cross-linked high molecular weight polymer.
Some of the compounds according to the invention, for instance the bis(diethylstilbestrol)hydrogen phosphate, may possess a certain oestrogenic effect. Such compounds may primarily be used in the cases where such an additional effect is desirable or without importance.